INTRODUCTION — Most cases of neutropenia are acquired and due to increased destruction, granulocyte apoptosis, or decreased granulocyte production. The congenital neutropenias, which will be discussed here, are much less common. A general discussion of neutropenia is presented separately. (See "Overview of neutropenia in children and adolescents".)
In addition to the congenital conditions associated with neutropenia presented below, some of these disorders are discussed separately in more detail:
●(See "Shwachman-Diamond syndrome".)
●(See "Cyclic neutropenia".)
●(See "Chediak-Higashi syndrome".)
●(See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".)
●(See "Primary humoral immunodeficiencies: An overview".)
●(See "Cartilage-hair hypoplasia".)
●(See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)'.)
Definition of neutropenia — Neutropenia in the adult is defined as an absolute neutrophil count (ANC) <1500/microL (<1.5 x 109/L). The ANC is equal to the product of the white blood cell count (WBC) and the fraction of polymorphonuclear cells (PMNs) and band forms noted on the differential analysis (calculator 1):
ANC = WBC (cells/microL) x percent (PMNs + bands) ÷ 100
Neutrophilic metamyelocytes and younger forms are not included in this calculation. The risk of infection begins to increase at an ANC <1000/microL (table 1).
Leukopenia and granulocytopenia are generally used interchangeably with neutropenia, although they are somewhat different. Leukopenia refers to a low WBC that may be due to lymphopenia as well as neutropenia, while granulocytopenia refers to a reduced number of granulocytes (neutrophils, eosinophils, and basophils).
Agranulocytosis literally means the absence of granulocytes, but the term is often used to indicate severe neutropenia (ie, ANC <200/microL).
Definition of congenital neutropenia — The term "congenital neutropenia" is somewhat confusing in the literature . "Congenital" neutropenia technically means any neutropenia present at or near birth, and thus would include transient immune neutropenias as well as inherited causes. We use the term to indicate neutropenia starting at or around birth and due to a primary bone marrow failure syndrome primarily involving the myeloid series. The term "congenital neutropenia" primarily refers to severe congenital neutropenia (SCN), with the Kostmann Syndrome (HAX1 mutation) as one subtype. In a broader sense, cyclic neutropenia and Shwachman-Diamond syndrome (SDS) are also included, although these disorders are usually referred to directly by their specific names (cyclic neutropenia, Shwachman-Diamond syndrome) [2-5]. Both cyclic neutropenia and SDS are discussed separately. (See "Cyclic neutropenia" and "Shwachman-Diamond syndrome".)
In addition to these disorders, there are now many recognized primary genetic defects that can result in serious chronic neutropenia with or without other immune deficiencies [1,2,5]. Most are characterized by a decreased bone marrow myeloid cell production, and an increased propensity to infection because of the resulting neutropenia. However, the neutropenia may be secondary to some other immune dysregulation and not a primary defect in production of neutrophils. Similarly, the propensity to infection may be due to an associated immune defect rather than the neutropenia itself. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia", section on 'Causes of neutropenia'.)
Clinical presentation — Patients present clinically with oropharyngeal problems, otitis media, respiratory infections, cellulitis, and skin infections, most often due to staphylococci and streptococci. Oral ulcerations and gingivitis are almost always present by two years of age in patients with severe neutropenia associated with decreased marrow reserve, although some children may also have stomatitis. Diffuse gastrointestinal lesions can give abdominal pain and diarrhea with a presentation mimicking Crohn disease . In comparison, infections with yeast, fungi, and parasites are infrequent in SCN, SDS, and cyclic neutropenia since other immune functions are intact. While congenital neutropenia patients can become septic, the propensity to overwhelming infection is not as severe as is seen in post-chemotherapy neutropenia.
Some patients have dysmorphic features or other associated physical findings . Hepatosplenomegaly and lymphadenopathy are generally not part of congenital neutropenia syndromes except as noted below . In general, any dysmorphic features in association with cytopenia should raise the possibility of an inherited bone marrow failure syndromes. Other clinical features of neutropenia with decreased marrow reserve are reviewed separately. (See "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia", section on 'Initial evaluation'.)
Laboratory findings — The neutropenia seen in the congenital neutropenias begins in infancy and is associated with decreased production of myelocytes and cells beyond myelocytes. Affected patients usually have isolated neutropenia with an ANC <500/microL. There may also be a relative monocytosis with monocyte percentage in the 30 to 50 percent range in some cases. At the time of the nadir of the neutrophil count in cyclic neutropenia there is a reciprocal monocytosis.
The hematologic presentations of these conditions are quite diverse. As an example, although all patients with SDS demonstrate varying degrees of bone marrow failure generally at an early age, some do not present until later in childhood, and approximately 10 percent do not have neutropenia. Patients with "MonoMAC" syndrome can present with only mild neutropenia and very low absolute monocytes counts, as discussed below and separately. (See 'GATA2 deficiency/MonoMAC syndrome' below and "Shwachman-Diamond syndrome", section on 'Cytopenias/infections'.)
Bone marrow findings — Bone marrow aspiration can be helpful in the differential diagnosis of congenital neutropenia. Bone marrow examination in SCN characteristically shows normal or somewhat decreased cellularity with an early myeloid "arrest" at the promyelocyte/myelocyte stage, often with atypical nuclei and cytoplasmic vacuolization. This bone marrow morphology is seen most typically in SCN due to mutations in ELANE, HAX1, WASP, G6PC3, and G-CSF receptors [1,6-9].
In contrast, the marrow in SDS, glycogen storage disease 1b, WHIM, Cohen disease, and Hermansky-Pudlak syndrome type 2 is not characteristic, but usually is hypocellular with decreased myeloid precursors . Some patients with SDS have involvement of other cell lines as well . Bone marrow aspiration is not at all helpful in CN as the findings depend on when in the cycle the bone marrow is sampled. If done at the onset of neutropenia, it is similar to SCN.
Some of the disorders noted below are T cell or B cell defects that result in neutropenia, often on an autoimmune basis, although a component of bone marrow failure may also be present. The bone marrow in antibody-mediated neutropenia will usually show normal cellularity with a late myeloid arrest or appear normal with neutrophils present or even increased. T cell disorders may show decreased marrow reserve. (See "Immune neutropenia" and "Overview of neutropenia in children and adolescents".)
Diagnostic features and making the diagnosis — The diagnosis of the congenital neutropenias can be guided by the presence of various clinical and laboratory features listed below. However, the final diagnosis in most cases rests on identification of the gene mutation and results of the bone marrow examination.
●Oculocutaneous albinism, peripheral neuropathy, and large granules in leukocytes – Chediak-Higashi syndrome
●Metaphyseal dysplasia, pancreatic insufficiency – Shwachman-Diamond syndrome
●Oculocutaneous albinism – Griscelli syndrome, Hermansky-Pudlak syndrome, p14 deficiency
●Significant splenomegaly – Autoimmune lymphoproliferative syndrome (ALPS)
●Warts – WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis syndrome)
●Monocytopenia, mild chronic neutropenia, and recurrent mycobacterial infections – MonoMAC syndrome
●Cyclic neutropenia – Cyclic neutropenia
●Hypoglycemia, growth retardation, hepatomegaly – Glycogen storage disease IB
●Short-limbed short stature, hypoplastic hair – Cartilage hair hypoplasia
●Skeletal myopathy, dilated cardiomyopathy – Barth's syndrome
●Hypotonia, microcephaly, intellectual disability – Cohen syndrome
●Cardiac and urogenital malformations, neurologic disorders – Glucose 6 phosphatase, catalytic subunit 3 (G6PC3) syndrome (but the phenotype is highly variable )
Several of the rare inherited neutropenia syndromes can be suspected by the presence of morphologically abnormal neutrophils on the peripheral blood smear (eg, giant cytoplasmic granules in the neutrophils in Chediak-Higashi syndrome, abnormal nuclear structure in the neutrophils in myelokathexis (picture 1)). (See 'Other inherited neutropenia syndromes' below and "Evaluation of the peripheral blood smear", section on 'White blood cells'.)
The diagnostic approach to neutropenia is evolving with more widespread availability of gene analysis. For patients with isolated neutropenia where a malignancy does not need to be ruled out immediately, we usually obtain a full bone marrow failure exome panel on peripheral blood before proceeding to bone marrow aspiration, especially in infants. Such panels contain nearly all genes that are known to cause bone marrow failure and they permit rapid identification of the cause of the neutropenia. The major barrier is getting insurance approval. For many cases, the diagnosis is established by genetic analysis and bone marrow examination is performed to determine cellularity and evaluate potential evolving malignant clones.
SEVERE CONGENITAL NEUTROPENIA
Epidemiology — Severe congenital neutropenia (SCN) is rare, with an estimated frequency of two to three cases per million population. There is no particular sex predilection. At least based on data from the United States, the majority of patients are White individuals [1,4,6,11,12]. The epidemiology of congenital neutropenia has been reviewed in detail [12,13].
Genetics and pathogenesis — SCN is a genetically transmitted disorder with recessive, dominant, or X-linked inheritance depending on which mutation is responsible:
●SCN due to mutations in the gene for neutrophil elastase (ELANE, previously called ELA2) is an autosomal dominant condition and occurs in 50 to 60 percent of patients [2,7,14-17].
●The initial family described by Kostmann, as well as other more recently described kindreds, have mutations in HAX1 with autosomal recessive inheritance [18-20].
●X-linked inheritance is seen in SCN due to mutations in the Wiskott-Aldrich syndrome (WAS) gene, also called WASP [17,21,22].
Mutations in more than 20 genes, including G6PC3, GFI1, SBDS, JAGN1, SRP54, and DNAJC21 have been described, but the genetic basis is not defined in approximately one-quarter of cases [21,23-28]. The pathogenesis of SCN from a historical and molecular basis has been reviewed, delineating the progression in our understanding of SCN in parallel with advances in understanding of the process of granulocyte differentiation [1,4,13,29].
It was originally suggested that the defect in SCN resulted from mutations in the granulocyte colony-stimulating factor (G-CSF) receptor gene, resulting in a truncated receptor . However, subsequent study revealed that this mutation is an acquired somatic mutation that may be associated with the development of acute leukemia (see 'Clinical features' below), but is clearly not the underlying basis for the disease itself.
The first mutations identified in SCN were in the neutrophil elastase gene (ELANE, formerly termed ELA2). To date, there are over 100 mutations identified based on data from the Severe Chronic Neutropenia International Registry. Several ELANE mutation sites have been reported [31-36]. In a study of 25 patients with congenital neutropenia, 22 had 18 different heterozygous mutations of the ELANE gene; mutations were not found in three patients with Shwachman-Diamond syndrome [31,32]. The genetic defects of SCN and other congenital neutropenias have been reviewed [1,4,12,13,21].
In reports of eight patients who were conceived from the same sperm donor, all children had the same mutation of ELANE (fourth exon at site S97L) and none of the mothers had an ELANE mutation [35,37]. Linkage analysis confirmed that all affected children had the same paternal allele leading to the expression of SCN, supporting the autosomal dominant inheritance of ELANE mutations.
The mutation in the original kindred described by Kostmann is in HAX-1 and is recessively transmitted. The HAX1 (HCLS1-associated X1) gene is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. A recurrent homozygous germline mutation in HAX1 has been found in a number of affected individuals with autosomal recessive SCN [18-20,38,39].
The expression of neutropenia in SCN may be either homogeneous or variable, according to the type of mutation and the genetic background, suggesting different pathogenetic mechanisms or, more likely, the effects of interacting genes [34,37].
Clinical features — SCN presents in infancy with an average absolute neutrophil count (ANC) <200/microL and often with elevated numbers of monocytes. There are no characteristic dysmorphic features. The clinical presentation has been described above. Other clinical features of SCN related to specific gene mutations are noted above.
The primary clinical feature in SCN is propensity to infection. (See 'Clinical presentation' above.)
Data from the Severe Chronic Neutropenia International Registry indicated a sepsis mortality of approximately 0.81 percent annually (95% CI 0.56-1.16 percent) . The cumulative incidence of death from sepsis after 15 years of therapy with G-CSF was 10 percent (95% CI 6-14 percent). There have been important findings relevant to diagnosis and management of patients from large registries in Europe and North America [12,13].
In the original description by Kostmann, 11 of the 14 patients died before their first birthday . Later follow up of this same cohort showed improved survival but development of neurological symptoms . The prognosis is now significantly better because of treatment with G-CSF. This agent results in improvement in the granulocyte counts in over 90 percent of patients.
However, now that the patients are surviving into adulthood, it is clear that malignant transformation of hematopoietic cells is a significant factor in overall survival. Patients with SCN have a predisposition to myelodysplastic syndrome (MDS) and leukemia, which is predominantly acute myeloid leukemia (AML), but also acute lymphoid leukemia, chronic myelomonocytic leukemia, and bi-phenotypic leukemia . Sequential acquisition of a series of mutations was documented in hematopoietic cells from a patient with SCN by serial exome sequencing . In a review of 374 patients enrolled in the Severe Chronic Neutropenia International Registry, 61 MDS/AML events were reported among 374 patients with SCN (16 percent) . The development of MDS/AML appears to be a complication of the underlying disease, unmasked by the increased survival with treatment, rather than a direct effect of G-CSF. (See 'Treatment' below.)
Treatment — The availability of G-CSF (filgrastim, lenograstim) therapy has dramatically changed management, resulting in a significant reduction in infections and improvement in the quality of life [6,7,45-47]. A reasonable approach is to start at 5 mcg/kg and escalate by 5 mcg/kg every three to five days until there is a response. It is important to note that G-CSF can induce cycling of the ANC that makes it hard to adjust the dose. Thus, if the ANC is erratic once a response has been obtained, it may be necessary to use a constant G-CSF dose for a few weeks and measure the ANC two to three times a week to determine whether the ANC is oscillating.
A response can be obtained in almost all patients, with most patients responding to a dose between 3 and 10 mcg/kg per day and fewer than 5 percent of patients not responding to 100 mcg/kg per day [48,49]. All responding patients have had reduced infections and a markedly improved quality of life. There have been few adverse effects other than splenomegaly, which occurred in 30 percent of patients; six patients underwent splenectomy for management of severe thrombocytopenia.
Examples of outcomes and doses of G-CSF used in clinical trials include the following:
●A multicenter, phase III trial randomly assigned 123 severely neutropenic patients (60 with SCN) to either immediate treatment with filgrastim (3.45 to 11.5 mcg/kg per day) or a four-month observation period followed by filgrastim treatment . Among the 120 patients given filgrastim, 108 had a median ANC greater than or equal to 1500/microL, four were partial responders, and eight failed to respond. Filgrastim therapy was associated with a reduction in the incidence and duration of infection-related events of approximately 50 percent.
●Patients involved in the phase I/II/III trials were continued on long-term maintenance treatment, and an international registry was established that had enrolled 374 patients with SCN through 2001 [6,40,50]. The median dose of filgrastim required to maintain an ANC greater than 1500/microL in patients with SCN was 5.6 mcg/kg per day, considerably higher than the doses required in patients with cyclic or idiopathic neutropenia. In comparison, granulocyte-macrophage colony-stimulating factor (GM-CSF) is much less likely to raise the ANC, and may instead increase eosinophil and monocyte counts .
The safety of chronic G-CSF administration continues to be an important issue. Two complications of concern are the development of malignancy and a high frequency of osteopenia and osteoporosis. Both appear to be complications of the underlying disease, but they may be exacerbated by G-CSF and/or unmasked by the increased survival with treatment. Patients with suboptimal responses to doses of G-CSF in excess of 6 mcg/kg per day had increased rates of sepsis mortality, as well as MDS/AML . The very high doses of G-CSF generally occurred in those children with subnormal ANCs in an attempt to "normalize" their ANC and prevent infection. This resulted in a wide spectrum of doses ranging from 0.2 to 576 mcg/kg per day. Follow-up on the SCN registry indicates that patients who failed to achieve an ANC >2188/microL (2.188 x 109/L) in spite of G-CSF doses above 8 mcg/kg/day were at elevated risk of sepsis, death, and MDS/AML.
●Patients in the low risk group had a cumulative risk of sepsis death after 15 years on G-CSF of 5 percent (95% CI 0-12 percent) and 15 percent (95% CI 4-25 percent) for MDS/AML.
●For those requiring more than 8 mcg/kg/day G-CSF, there was an 18 percent (95% CI 7-28 percent) sepsis risk and 34 percent (95% CI 21-47 percent) for MDS/AML .
Although treatment of SCN patients with an appropriate dose of G-CSF can reverse neutropenia and reduce the risk of sepsis, these patients are still at risk to succumb to sepsis . Death from sepsis in treated SCN patients may reflect myelosuppression by intercurrent illness or lapses in therapy due to non-adherence.
A high incidence of bone loss has been found in patients treated with G-CSF for SCN [52,53]. In one series, for example, bone mineral content was found to be significantly reduced in 15 of 30 patients  and is a known adverse effect of G-CSF treatment [1,54]. Accordingly, bone density, as well as 25-OH vitamin D levels should be monitored and osteoporosis treated as indicated. (See "Bone physiology and biochemical markers of bone turnover".)
In a cohort of 21 women in the International SCN registry (38 pregnancies), the majority (81 percent) received G-CSF during at least part of their pregnancy . The therapy was generally well-tolerated, and no bacterial infections were reported. There were 31 live births (82 percent) and five preterm deliveries (13 percent). Of 25 newborns born to parents with ELANE mutations, 15 had neutropenia.
Hematopoietic cell transplantation — Hematopoietic cell transplantation (HCT; also referred to as hematopoietic stem cell transplantation [HSCT]) is potentially curative and should be considered for all patients with SCN, particularly those with a high requirement for G-CSF (eg, >8 to 10 mcg/kg/day), those unable to tolerate G-CSF, or those with continued infections despite G-CSF therapy [40,56-60]. The overall survival is approximately 80 percent, though it may be better for patients treated less than 10 years of age and those treated since 2008. However, chronic graft-versus-host disease occurred in 20 percent and there is 10 percent graft failure .
Not all patients who would benefit from HCT will have access to this therapy, which requires a compatible donor. However, the marked advancements in unrelated donor and haplo-identical transplant in the past decade favor consideration of transplant in most if not all patients. (See "Donor selection for hematopoietic cell transplantation".)
Prognosis — Prior to the advent of recombinant G-CSF, patients were conventionally treated with antibiotics for specific infections. The administration of prophylactic antibiotics, particularly trimethoprim-sulfamethoxazole, was common. Most patients died at a relatively early age. Prognosis has improved since use of G-CSF (and in some cases HCT) has been incorporated into therapy; however, as noted above, deaths from sepsis or complications from HCT may occur.
OTHER INHERITED NEUTROPENIA SYNDROMES
Shwachman-Diamond syndrome — The triad of neutropenia, metaphyseal dysplasia, and pancreatic insufficiency is known as the Shwachman-Diamond (or Shwachman-Bodian-Diamond or Shwachman-Diamond-Oski) syndrome. The degree of neutropenia in this syndrome is variable, but moderate. Many patients do not require regular treatment with granulocyte colony-stimulating factor (G-CSF). This disorder is discussed separately. (See "Shwachman-Diamond syndrome".)
WHIM syndrome — WHIM syndrome (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) is a disorder in which a mutant CXCR4 chemokine receptor causes abnormal apoptosis and migratory function, with retention of mature neutrophils in the bone marrow. Clinical features vary and may include neutropenia, lymphopenia, hypogammaglobulinemia, and warts due to human papilloma virus infection. These patients are often severely neutropenic even though the bone marrow may be hypercellular, suggesting impaired release of neutrophils from the bone marrow (kathexis = retention). Many cells in the marrow are hypersegmented with abnormally long chromatin filaments connecting the nuclear lobes, have an unusual shape, and contain degenerative pyknotic nuclei and cytoplasmic vacuoles (ie, myelokathexis) (picture 1). The use of G-CSF and/or plerixafor to increase neutrophil counts, and other aspects of the comprehensive management of WHIM syndrome, are discussed separately. (See "Epidermodysplasia verruciformis", section on 'WHIM syndrome'.)
GATA2 deficiency/MonoMAC syndrome — Mutations of GATA2, which encodes a key hematopoietic transcription factor, may be associated with mild chronic neutropenia (median absolute neutrophil count [ANC] 1500) and profound monocytopenia (median 14.5 cells/microL normal >210) . Mutations of GATA2 may be associated with a wide variety of hematopoietic and/or somatic manifestations (eg, MonoMac syndrome, Emberger syndrome) , as described separately. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)' and "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial MDS/AML with mutated GATA2'.)
Chediak-Higashi syndrome — Chediak-Higashi syndrome is a rare inherited disorder characterized by oculocutaneous albinism, progressive peripheral neuropathy, frequent neutropenia, and a tendency to develop life-threatening hemophagocytic lymphohistiocytosis. Neutrophils have characteristic large granules that are diagnostic. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis" and "Chediak-Higashi syndrome".)
Glycogen storage disease type 1b — Glycogen storage disease (GSD) type 1, also known as von Gierke disease, is caused by a deficiency in microsomal glucose-6-phosphatase (G6P-ase) activity. (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".) There are four subgroups: 1a, 1b, 1c, and 1d. Type 1a results from mutations in the G6P-ase gene on chromosome 17, while the defective gene for types 1b and 1c map to chromosome 11q23 [63,64].
Neutropenia occurs in types 1b and 1c, but only patients with type 1b suffer infectious complications, which are due to functional neutrophil deficiency, neutropenia, and the presence of circulating apoptotic neutrophils . It has been suggested that microsomal glucose-6-phosphate transport has a role in the antioxidant protection of neutrophils, and that the genetic defect of the transporter leads to impaired neutrophil cellular function and apoptosis .
Congenital cobalamin deficiencies — There are a number of inherited defects that interfere with the normal absorption, subsequent cellular processing, and transport of cobalamin (vitamin B12) . All are associated with the presence of megaloblastic anemia typical of pernicious anemia, usually with mild degrees of neutropenia. (See "Treatment of vitamin B12 and folate deficiencies".)
Immunologic disorders — Neutropenia is seen in approximately 25 percent of patients with X-linked agammaglobulinemia and some patients with the hyperimmunoglobulin M syndrome . Many patients with these disorders benefit from the use of intravenous immune globulin. (See "Primary humoral immunodeficiencies: An overview" and "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)
Neutropenia is also a feature of reticular dysgenesis, a form of severe combined immunodeficiency characterized by absence of all leukocytes. (See "Severe combined immunodeficiency (SCID): Specific defects", section on 'Reticular dysgenesis'.)
G-CSF receptor mutations — Germline mutations of the G-CSF receptor (CSF3R) only rarely cause neutropenia in severe congenital neutropenia (SCN) [69,70]. However, acquired CSF3R mutations may contribute to the development of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) in patients with SCN, even though its role in leukemogenesis in this setting is not well understood [7,71,72]. In three series, 11 of 15 patients with SCN who acquired a G-CSF receptor point mutation developed AML or MDS [6,30]. However, point mutations are neither a prerequisite nor a direct cause for AML or MDS since not all patients who develop AML have a mutation , a mutation can be present without AML , or the mutation can spontaneously disappear . It is possible that mutations in the G-CSF receptor predispose to AML via a resistance to apoptosis , allowing more time for a "second hit" mutation to occur .
It has been speculated that G-CSF therapy might increase the risk of AML, especially in patients who harbor CSF3R mutations [76,77], in light of the hyperproliferative response to G-CSF observed in mutant mice. Conversely, G-CSF may not be involved in leukemogenesis in these patients, since AML also occurs in those who are untreated [78,79], and AML/MDS has not developed in patients with cyclic or idiopathic neutropenia treated with G-CSF [6,77]. (See "Cyclic neutropenia".)
Cyclic neutropenia — Cyclic neutropenia, in contrast to other congenital neutropenias, tends to be less severe, but children with cyclic neutropenia remain at risk for sepsis if not treated with G-CSF. During periods of neutropenia, patients with cyclic neutropenia remain vulnerable to gingivitis and mouth ulcers. This entity is discussed in detail separately. (See "Cyclic neutropenia".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone marrow failure syndromes".)
●The term "congenital neutropenia" is used here to indicate neutropenia starting at or around birth, due to a primary bone marrow failure syndrome. It refers primarily to the following three conditions:
•Severe congenital neutropenia (SCN) (see 'Severe congenital neutropenia' above)
•Cyclic neutropenia (see "Cyclic neutropenia")
•Shwachman-Diamond syndrome (SDS) (see "Shwachman-Diamond syndrome")
●There are many additional primary genetic defects with serious chronic neutropenia with or without other immune deficiencies. Most are characterized by a decreased bone marrow reserve pool and an increased propensity to infection. (See 'Other inherited neutropenia syndromes' above and "Overview of neutropenia in children and adolescents" and "Approach to the adult with unexplained neutropenia", section on 'Causes of neutropenia'.)
●Patients with congenital neutropenias present clinically with oropharyngeal problems, otitis media, respiratory infections, cellulitis, and skin infections, most often due to staphylococci and streptococci. Oral ulcerations and painful gingivitis are almost always present by two years of age. (See 'Clinical presentation' above.)
●Patients with congenital neutropenias usually have isolated neutropenia with an absolute neutrophil count (ANC) <500/microL. Bone marrow examination in SCN characteristically shows normal or somewhat decreased cellularity with an early myeloid arrest at the promyelocyte/myelocyte stage. (See 'Laboratory findings' above and 'Bone marrow findings' above.)
●The diagnosis of the congenital neutropenias may be guided by the presence of associated clinical features, although the final diagnosis rests on identification of the gene mutation and results of the bone marrow examination. (See 'Diagnostic features and making the diagnosis' above and 'Bone marrow findings' above.)
●The availability of granulocyte colony-stimulating factor (G-CSF) has resulted in a significant reduction in infections and improvement in the quality of life for many patients with SCN. (See 'Treatment' above.)
●Hematopoietic cell transplantation may be appropriate for selected patients with SCN, such as those with a high G-CSF requirement. (See 'Hematopoietic cell transplantation' above.)
●Other hereditary neutropenias besides SCN include a number of rare conditions discussed above. (See 'Other inherited neutropenia syndromes' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges the extensive contributions of Donald H Mahoney, Jr, MD to earlier versions of this topic review.
The UpToDate editorial staff also acknowledges the late Laurence A Boxer, MD, for his previous role as a section editor for this topic.
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62 : High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia.
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66 : Inhibition of microsomal glucose-6-phosphate transport in human neutrophils results in apoptosis: a potential explanation for neutrophil dysfunction in glycogen storage disease type 1b.
69 : Deletional mutation of the external domain of the human granulocyte colony-stimulating factor receptor in a patient with severe chronic neutropenia refractory to granulocyte colony-stimulating factor.
71 : Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey.
72 : Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia.
73 : Long-term follow-up of granulocyte colony-stimulating factor receptor mutations in patients with severe congenital neutropenia: implications for leukaemogenesis and therapy.
74 : Mutations of the granulocyte-colony stimulating factor receptor in patients with severe congenital neutropenia are not required for transformation to acute myeloid leukaemia and may be a bystander phenomenon.
75 : Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival.
77 : Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy.
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